Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases

Chang, Andrew; Xiang, Xinyu; Wang, Jing; Lee, Carolyn; Arakhamia, Tamta; Simjanoska, Marija; Wang, Chi; Carlomagno, Yari; Zhang, Guoan; Dhingra, Shikhar; Thierry, Manon; Perneel, Jolien; Heeman, Bavo; Forgrave, Lauren M.; DeTure, Michael; DeMarco, Mari L.; Cook, Casey; Rademakers, Rosa; Dickson, Dennis W.; Petrucelli, Leonard; Stowell, Michael H. B.; Mackenzie, Ian R.; Fitzpatrick, Anthony

doi:10.1016/j.cell.2022.02.026

Cited by 80 publications

(117 citation statements)

References 74 publications

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“…Pathological deposits of filamentous protein in neurons and glia have been detected in multiple neurodegenerative diseases, including α-synuclein in PD and amyloid-β (Aβ) and tau in Alzheimer’s disease (AD) [ 69 ]. These neurodegeneration studies have identified “one conformer per disease” paradigm, with the presence of unknown buried cofactors and diverse patterns of posttranslational modification mediating the structural diversity of fibrillar polymorphs [ 143 , 144 ]. Notably, Hb chains have been detected in various neurons and glial cells in the brain and are associated with different proteinopathies of neurodegenerative diseases [ 145 , 146 ].…”

Section: Commonality Of Amyloid Fibrils With Hemoglobin In Neurodegen...mentioning

confidence: 99%

Physiological and Pathological Functions of Neuronal Hemoglobin: A Key Underappreciated Protein in Parkinson’s Disease

Zheng

Yan

et al. 2022

IJMS

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The expression of Hemoglobin (Hb) is not restricted to erythrocytes but is also present in neurons. Hb is selectively enriched in vulnerable mesencephalic dopaminergic neurons of Parkinson’s disease (PD) instead of resistant neurons. Controversial results of neuronal Hb levels have been reported in postmortem brains of PD patients: although neuronal Hb levels may decline in PD patients, elderly men with higher Hb levels have an increased risk of developing PD. α-synuclein, a key protein involved in PD pathology, interacts directly with Hb protein and forms complexes in erythrocytes and brains of monkeys and humans. These complexes increase in erythrocytes and striatal cytoplasm, while they decrease in striatal mitochondria with aging. Besides, the colocalization of serine 129-phosphorylated (Pser129) α-synuclein and Hb β chains have been found in the brains of PD patients. Several underlying molecular mechanisms involving mitochondrial homeostasis, α-synuclein accumulation, iron metabolism, and hormone-regulated signaling pathways have been investigated to assess the relationship between neuronal Hb and PD development. The formation of fibrils with neuronal Hb in various neurodegenerative diseases may indicate a common fibrillization pathway and a widespread target that could be applied in neurodegeneration therapy.

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Section: Commonality Of Amyloid Fibrils With Hemoglobin In Neurodegen...mentioning

confidence: 99%

Physiological and Pathological Functions of Neuronal Hemoglobin: A Key Underappreciated Protein in Parkinson’s Disease

Zheng

Yan

et al. 2022

IJMS

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“…Recent advances in cryogenic electron microscopy (cryo-EM) have enabled researchers to identify the structure of fibrils extracted from postmortem brain tissue, and over the past years the structure of pathological forms of filaments formed by tau (reviewed in [ 60 ]), amyloid-β [ 31 ], α-synuclein [ 58 ], and TDP-43 [ 2 ] have been determined. Several independent cryo-EM groups now report amyloid fibrils in brain tissue of a diverse set of neurodegenerative disorders as well as older neurologically normal individuals to comprise the C-terminal domain (AA120-254/274) of transmembrane protein 106B (TMEM106B), a protein previously shown to modulate disease risk in neurodegeneration and implicated in healthy aging [ 10 , 17 , 27 , 57 ].…”

Section: Introductionmentioning

confidence: 99%

“…Over the past months, several research groups have reported the cryo-EM structures of TMEM106B filaments derived from the brains of a variety of neurodegenerative diseases as well as older neurologically normal individuals [ 10 , 17 , 27 , 57 ]. The cryo-EM reports included fibrils obtained from sarkosyl-insoluble fractions of postmortem tissue of individuals with Alzheimer’s disease (AD), argyrophilic grain disease (AGD), amyotrophic lateral sclerosis (ALS), aging-related tau astrogliopathy (ARTAG), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), dementia with Lewy bodies (DLB), early-onset Alzheimer’s disease (EOAD), sporadic and inherited Parkinson’s disease (PD), PD dementia (PDD), inherited and sporadic frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) type A, B, C, D, familial frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17T), limbic-predominant neuronal inclusion body 4R tauopathy (LNT), multiple system atrophy (MSA), pathological aging (PA), as well as neurologically normal controls (Fig.…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, the identification of TMEM106B was distinct between groups. Whereas Chang et al [ 10 ] complemented the cryo-EM with mass spectrometry to identify TMEM106B peptides present in the sarkosyl-insoluble fraction, Jiang et al [ 27 ] modeled two query sequences based on the cryo-EM densities, and Schweighauser and colleagues [ 57 ] found their way to TMEM106B based on the fibril’s distinctive glycosylation pattern.…”

Section: Introductionmentioning

confidence: 99%

“…All cryo-EM studies report TMEM106B to be fully glycosylated in all folds at the glycosylation sites present within the fibrillar structure (N145, N151, N164, and N183), and the presence of a disulfide bond between C214 and C253. The structural variation between polymorphisms is mainly located in the middle region and C-terminal region [ 10 , 27 , 57 ]. The high number of β-strands results in a highly stable fibril core, which could potentially be irreversible once formed, as suggested by Jiang et al [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

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Identification of TMEM106B amyloid fibrils provides an updated view of TMEM106B biology in health and disease

Perneel

Rademakers

2022

Acta Neuropathol

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Since the initial identification of TMEM106B as a risk factor for frontotemporal lobar degeneration (FTLD), multiple genetic studies have found TMEM106B variants to modulate disease risk in a variety of brain disorders and healthy aging. Neurodegenerative disorders are typically characterized by inclusions of misfolded proteins and since lysosomes are an important site for cellular debris clearance, lysosomal dysfunction has been closely linked to neurodegeneration. Consequently, many causal mutations or genetic risk variants implicated in neurodegenerative diseases encode proteins involved in endosomal–lysosomal function. As an integral lysosomal transmembrane protein, TMEM106B regulates several aspects of lysosomal function and multiple studies have shown that proper TMEM106B protein levels are crucial for maintaining lysosomal health. Yet, the precise function of TMEM106B at the lysosomal membrane is undetermined and it remains unclear how TMEM106B modulates disease risk. Unexpectedly, several independent groups recently showed that the C-terminal domain (AA120-254) of TMEM106B forms amyloid fibrils in the brain of patients with a diverse set of neurodegenerative conditions. The recognition that TMEM106B can form amyloid fibrils and is present across neurodegenerative diseases sheds new light on TMEM106B as a central player in neurodegeneration and brain health, but also raises important new questions. In this review, we summarize current knowledge and place a decade’s worth of TMEM106B research into an exciting new perspective.

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Gene replacement‐Alzheimer's disease (GR‐AD): Modeling the genetics of human dementias in mice

Benzow,

Karanjeet,

Oblak

et al. 2024

Alzheimer's & Dementia

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INTRODUCTIONGenetic studies conducted over the past four decades have provided us with a detailed catalog of genes that play critical roles in the etiology of Alzheimer's disease (AD) and related dementias (ADRDs). Despite this progress, as a field we have had only limited success in incorporating this rich complexity of human AD/ADRD genetics findings into our animal models of these diseases. Our primary goal for the gene replacement (GR)‐AD project is to develop mouse lines that model the genetics of AD/ADRD as closely as possible.METHODSTo do this, we are generating mouse lines in which the genes of interest are precisely and completely replaced in the mouse genome by their full human orthologs.RESULTSEach model set consists of a control line with a wild‐type human allele and variant lines that precisely match the human genomic sequence in the control line except for a high‐impact pathogenic mutation or risk variant.

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Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases

Cited by 80 publications

References 74 publications

Physiological and Pathological Functions of Neuronal Hemoglobin: A Key Underappreciated Protein in Parkinson’s Disease

Physiological and Pathological Functions of Neuronal Hemoglobin: A Key Underappreciated Protein in Parkinson’s Disease

Identification of TMEM106B amyloid fibrils provides an updated view of TMEM106B biology in health and disease

Gene replacement‐Alzheimer's disease (GR‐AD): Modeling the genetics of human dementias in mice

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